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Ewing sarcoma is defined as a high grade tumor composed of round cells without neuroectodermal features, as assessed by immunohistochemistry (e.g., no reactivity to chromoganin or synaptophysin) and electron microscopy (no neurosecrectory granules).1,2 Primitive neuroectodermal tumor (PNET) is a counterpart with neuroectodermal differentiation; it is common to consider ES and PNET together as ends of the same neoplastic spectrum. Now a day, both tumors are designated as "Ewing Sarcoma Family Tumors" (ESFT). The ESFT is characterized by a t(11;22)(q24;q12) chromosomal translocation in the majority of cases, that encodes an oncogenic fusion protein EWS/FLI1 in more than 80% of the cases.3,4 Besides the EWS/FLI1 fusion, there are other fused proteins, due to other translocations, in about 5-10% of cases, with EWS gene breakdown involved in all molecular events of ES.3
Most cases of ESTF arises in the bones, mainly in the long bones and pelvis,5 affecting mostly adolescents and young adults6. Up to 30% of these lesions can be found in soft tissues, mostly in the extremities, and this variant is associated with older patients and metastatic disease, as compared to conventional osseous tumors, although the prognosis is quite similar.7,8
Up to 9% of ESFT cases arise in the head and neck region.5,9 To the best of our knowledge, only six cases of extraosseous variant affecting the oral cavity have been documented, as follows: in the soft tissue anterior to the mandibular symphysis10, in the hard palate11, submandibular gland12, tongue13, floor of the mouth9, and in the cheek14. Because of this, treatment approach for these tumors is based on that offered to the skeletal counterpart. Therefore, there is no conclusive data about their prognosis. This work describes an additional extraosseous ES affecting the retromolar mucosa of the mandible with extension to the cheek and late bone invasion, in an adult male patient.
A 41-year-old Caucasian male patient was admitted to our Stomatology service (2007) with a painless swelling in the face, with three months of duration. He related a few episodes of fever and pain during this period of time; past medical and familial history was noncontributory. The patient presented with swelling and asymmetry on the left side of his face. An oral examination revealed a firm nodular swelling beneath the normal overlying mucosa in the retromolar region, with a multilobular aspect, extending to the cheek on the left side (Figure 1C). Panoramic radiograph evidenced an infiltrative and undefined radiolucency aspect in the mandible, revealing a heterogeneous and poorly organized trabecular bone in the left region. Axial and coronal computerized tomography images showed a well-defined soft tissue tumor involving the region of the buccal mucosa (Figure 3A and 3C).
The patient underwent incisional biopsy of the mass lesion; the analysis revealed an infiltrate of small round cells with round nuclei containing fine chromatin, with the formation of clusters of neoplastic cells with undefined delimitations (Figure 2A). Tumor stroma was scarcely vascularized, and the neoplastic cells were scattered within the fibrous connective tissue disposed as ill-defined agglomerate of varied forms and dimensions. The small-sized neoplastic cells showed a high nuclei/cytoplasm ratio and occasional nucleoli that seemed to be small. In some areas, round clear cells with well-delimited cytoplasm could also seem. In general, tumor cells presented little atipia, but a dense mitotic rate could be noted (Figure 2B). Small focuses of necrosis was found sparsely distributed throughout the neoplastic tissue.
Immunohistochemistry revealed positivity to CD99 (Figure 2C), vimentin (Figure 2D), and neuron specific enolase (NSE) (Figure 2E). The CD99 was preferentially found on cellular membranes; vimentin and NSE immunostaining were respectively diffusely found in a highly and moderately intensity on cytoplasm. In addition, there was a slight positivity to AE1/AE3 cytokeratin (Figure 2F) and cromoganin. On the other hand, CD57, Epithelial Membrane Antigen (EMA), and Leukocyte Common Antigen (LCA) were negative. Based on these findings a hiatopathological and immunohistochemical diagnosis of extraosseous Ewing Sarcoma Tumor Family was strongly suggested.
The diagnosis was confirmed by fluorescent in situ hybridization (FISH) analysis, using an EWS break-apart probe (LSI EWSR Dual Color Breakapart DNA probe; VysisÂ®) according to the supplier's instructions. The cells showed one normal EWS gene signal (red/green or yellow) and one split EWS signal (Figure 2G).
The patient was treated with multi-agent chemotherapy for one year, using ifosfamide, dexamethasone, and etoposide, combined with 5040 cGy of radiotherapy. Five years later, clinical examination of the patient revealed absence of asymmetry, swelling, and signs and symptoms of the disease. Further, a complete patient work up with MRI and CT scans revealed no evidence of recurrence and metastases.
Extraosseous ESTF (EOESTF) is a rare soft tissue tumor that is morphologically indistinguishable from the more common Ewing sarcoma of the bone.15 Studies found in the literature show a range of 1-4%16 and 1-9%9 in terms of cases in the head and neck region. EOESTF in the head and neck region is even rarer, with studies revealing 4.7% of all cases founded in 42 patients.8 Oral cavity is rarely affected. The adverse prognosis has been being related to patients older than eighteen years, with tumors greater than 8 centimeters, mostly those with metastases.17
About the case reported in this paper, some peculiarities concerning the tumor site and age of patient are discussed. The oral cavity involvement and age after the fourth decade of life, very uncommon in cases of ES, revealed a single evolution, not reported elsewhere. Besides the gender and race of the patient is in accordance with the literature, as seen in a study that reported a predilection in reference to white males in 683 cases of EOESTF18, the progression of the disease and the response to the treatment were favorable.
In addition, in reference to EOESTF of the oral cavity, the cases do not follow a pattern, with all of them presenting specific features that do not allow them to be placed in a group and studied together. Kang et al. (2005)11 reported a case involving a 34-year-old male patient with painless swelling in the hard palate; Agir et al. (2007)12 reported a case of a 22-year-old male patient with a well-defined soft tissue tumor arising from the submandibular gland; Whaley et al. (2010)9, in a series of cases, reported on a case of EES in the floor of the mouth in an eight-year-old female patient and Sahin et al. (2011)14 reported on a case of a 23-year-old male patient with a painless mass on his cheek. When those cases are compared with the one reported in this article, the only patient older than 30 years was our patient (41 years old); in addition, the site of involvement, the retromolar region, has not been reported elsewhere. In the study of Xie, Liu and Xi (2010)19 they reported a case in the submandibular area, in a series of 18 EOESTF cases, with no specification of the involvement of oral cavity, then, excluded of our analysis.
The course of the lesion was rapid, with an extension to the buccal mucosa occurring as a progression of the disease, revealing an active growth. These inconsistencies in terms of clinical findings may lead to a difficult diagnosis.
In addition, it is known that the Ewing sarcoma family of tumors can represent a challenge in reference to diagnosis and management, given the rarity of these tumors in adults; moreover, it is important to emphasize that 80% of cases will occur during the first two decades of life.20
In our case, the tumor showed an expansive pattern, with progression to the cheek and involvement of adjacent bone at the first three months. The other cases reported reveal an average time of complaint of about two to four months, which was the only feature that was similar in all cases. However, the fever was only reported in 6.6% of the patients in a study of 226 cases of ES.21
About the histophatological features, all of the findings are in agreement with the other studies of ES and EES. The case reported revealed similar characteristics in agreement with the report of Kennedy et al. (2000)1 which revealed microscopic sheets and nests of round cells with variably prominent nuclei and a thin rim of eosinophilic cytoplasm; there were also frequent mitotic figures, in accordance with the histological aspects found in a literature review of these cases. The strong positivity of CD99, revealing a characteristic membranous fashion, and the positivity to NSE and Vimentin also were important features in the delineation of the ES hypothesis.
Additionally, as in other studies in the literature, the differential diagnosis from other round-cell tumors was difficult to establish and the cytogenetic and molecular genetic findings were important in the implementation of the correct diagnosis. The EWS breakdown found in our case improved the diagnosis and reinforced the sets of histological and molecular findings in terms of ES. Likewise, Hanaoka et al. (2011)22 reported that the cytogenetic and molecular genetic findings of translocation leading to the fusion of the EWS gene on 22q12 are defining features of ES/Primitive neuroectodermal tumors. Also, van de Rijn and Fletcher (2006)3 explained that the translocations involving the EWS gene are considered essential genetic aberrations in ES tumors and that the split in the EWS region is present in 100% of the cases, with the t(11;22)(q24;q12) resulting in a EWS-FLI1 fusion present in more than 80% of the tumors.
Concerning the treatment of our patient, chemotherapy plus radiotherapy showed great results, with five years of continuous attendance and no signal of clinical recurrence. Allam et al. (1999)16 reported that an initial biopsy, followed by combined systemic chemotherapy plus radiotherapy to the primary site involved were done in 58% of 24 patients diagnosed with ES in the head and neck region, with great results; Kang et al. (2005)11 showed that early and confident diagnoses, coupled with modern chemo and radiotherapy, has greatly improved the prognosis for patients with ES/Primitive Neuroectodermal tumors. The drugs used in this specific treatment have already been reported, revealing important results. Jürgens and Dirksen (2011)23 reported that most combination chemotherapy regimens are based on alkylating agents, primarily ifosfamide, cyclophosphamide, and anthracyclines, with the addition of vinca alkaloids and actinomycin D and etoposide.
Due to the difficulties in classifying Ewing sarcomas and the paucity of cases in the head and neck region, a proper diagnosis is difficult to ascertain. Immunohistochemical and molecular techniques have to be employed to attempt the delineation of the correct diagnosis and the introduction of adequate therapy in these cases. In relation to EES in the head and neck, especially in oral cavity, it is observed that the lack of pathognomonic aspects, concerning the clinical features, leaves to an difficulty in the establishment of the diagnosis and reveal a inconstancy in the behavior of these lesions.